The hepatic function of cholesterol sulfotransferase 2B1b (SULT2B1b)in energy met

胆固醇磺基转移酶2B1b（SULT2B1b）在能量代谢中的肝功能

• 批准号: 9087207
• 负责人: Wen Xie
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9087207
• 关键词: Acetate-CoA Ligase; Acetylation; Alkanesulfonates; Binding; Breeding; Cholesterol; Data; Down-Regulation; Eating; Energy Metabolism; Enzymes; Event; Exclusion; Fasting; Feedback; Gene Expression; Gene Targeting; Genes; Gluconeogenesis; Goals; Health; Hepatic; Hepatocyte; Homeostasis; Human; In Vitro; Insulin Resistance; Leptin; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Translocation; Obese Mice; Obesity; Oxygen Consumption; Play; Production; Regulation; Role; SULT2B1; Testing; Therapeutic Agents; Transgenes; Transgenic Mice; Transgenic Organisms; Xenobiotics; base; cholesterol sulfotransferase; cholesteryl sulfate; feeding; glucose metabolism; improved; in vivo; insulin sensitivity; lipid metabolism; meetings; new therapeutic target; overexpression; promoter; sulfation; sulfotransferase

DESCRIPTION (provided by applicant): The cholesterol sulfotransferase SULT2B1b is a cytosolic sulfotransferase best known for its activity in sulfonating cholesterol and oxysterols. Metabolic syndrome, often manifested as obesity and insulin resistant type 2 diabetes, is a major health concern. The dysregulation of glucose and lipid metabolism plays an important pathogenic role in obesity and type 2 diabetes. Although the activity of SULT2B1b in catalyzing the sulfation of cholesterol has been documented, the role of SULT2B1b and its enzymatic byproduct cholesterol sulfate (CS) in energy metabolism and metabolic syndrome remains largely unknown. Our preliminary results showed that: 1) SULT2B1b was induced in obese mice and during the transition from the fasted to the fed state; 2) SULT2B1b and CS inhibited gluconeogenesis in hepatic cells; 3) SULT2B1b and CS specifically inhibited the gluconeogenic activity of HNF4α; 4) Treatment with CS inhibited gluconeogenesis and improved insulin sensitivity in both HFD and ob/ob models; 5) Transgenic overexpression of SULT2B1b improved metabolic functions in the HFD model; 6) Leptin is a potential effector for the metabolic benefit of SULT2B1b; 7) SULT2B1b and CS suppressed the expression of acetyl-coenzyme A synthetase 2 (Acss2), decreased the acetylation of HNF4α, and caused the nuclear exclusion of HNF4α; whereas a forced expression of Acss2 abolished the inhibitory effect of CS on HNF4α; 8) Down-regulation of HNF4α abolished the inhibitory effect of CS on gluconeogenesis in vitro; and 9) SULT2B1b is a potential HNF4α target gene, providing a possible mechanism of negative feedback regulation of gluconeogenesis. Based on our preliminary data, we hypothesize that the cholesterol sulfotransferase SULT2B1b has a previously unrecognized role in inhibiting gluconeogenesis and alleviating metabolic disease. Mechanistically, the metabolic benefit of SULT2B1b may have been achieved through its enzymatic byproduct cholesterol sulfate (CS) and by targeting the acetylation and nuclear translocation of the gluconeogenic transcriptional factor HNF4α. We also hypothesize that the SULT2B1 is a HNF4α target gene, which represents a negative feedback mechanism to limit the gluconeogenic activity of HNF4α. We anticipate that leptin is a potential effector of SULT2B1b in improving metabolic functions. By using the liver-specific SULT2B1b transgenic mice, in conjunction with HFD and ob/ob models of obesity and type 2 diabetes, we propose three Specific Aims to test our hypotheses: 1) To determine whether the liver-specific overexpression of SULT2B1b inhibits the ob/ob model of obesity and type 2 diabetes; 2) To determine the molecular mechanism by which SULT2B1b and CS inhibit gluconeogenesis; and 3) To determine whether the induction of SULT2B1b by HNF4α represents a potential mechanism of negative feedback regulation of gluconeogenesis. To our knowledge, this study represents the first attempt to comprehensively evaluate the endobiotic and hepatic function of SULT2B1b and its enzymatic byproduct CS in energy metabolism in vivo. Results from this study may establish SULT2B1b as a novel therapeutic target and CS as a therapeutic agent to manage metabolic disease.

描述（由申请人提供）：胆固醇磺基转移酶 SULT2B1b 是一种胞质磺基转移酶，以其磺化胆固醇和氧化甾醇的活性而闻名。代谢综合征通常表现为肥胖和胰岛素抵抗 2 型糖尿病，是一个主要的健康问题。尽管SULT2B1b的活性在肥胖和2型糖尿病中起着重要的致病作用。 SULT2B1b 催化胆固醇的硫酸化已被记录，但 SULT2B1b 及其酶副产物胆固醇硫酸盐 (CS) 在能量代谢和代谢综合征中的作用仍然很大程度上未知。我们的初步结果表明：1) SULT2B1b 在肥胖小鼠中和在过渡期间被诱导。从禁食状态到进食状态；2) SULT2B1b 和 CS 抑制肝细胞中的糖异生；抑制 HNF4α 的糖异生活性；4) 在 HFD 和 ob/ob 模型中，CS 治疗可抑制糖异生并改善胰岛素敏感性；5) SULT2B1b 的转基因过度表达可改善 HFD 模型中的代谢功能；6) 瘦素是SULT2B1b 的代谢益处；7) SULT2B1b 和 CS 抑制乙酰辅酶 A 合成酶 2 的表达(Acss2)，降低HNF4α的乙酰化，并导致HNF4α的核排斥；而Acss2的强制表达消除了CS对HNF4α的抑制作用；8) HNF4α的下调消除了CS对体外糖异生的抑制作用。 ; 9) SULT2B1b 是一个潜在的 HNF4α 靶基因，根据我们的初步研究，它提供了一种可能的糖异生负反馈调节机制。根据数据，我们发现胆固醇磺基转移酶 SULT2B1b 在抑制糖异生和减轻代谢疾病方面具有先前未被认识的作用。从机制上讲，SULT2B1b 的代谢益处可能是通过其酶副产物硫酸胆固醇 (CS) 以及靶向乙酰化和核转位来实现的。我们还发现 SULT2B1 是一个糖异生转录因子 HNF4α。 HNF4α 靶基因，代表限制 HNF4α 糖异生活性的负反馈机制，通过使用肝脏特异性 SULT2B1b 转基因小鼠，结合 HFD 和 ob/，我们预计瘦素是 SULT2B1b 改善代谢功能的潜在效应器。通过肥胖和 2 型糖尿病的 ob 模型，我们提出了三个具体目标来检验我们的假设：1) 确定 SULT2B1b 的肝脏特异性过度表达是否会抑制肥胖和 2 型糖尿病的 ob/ob 模型；2) 确定 SULT2B1b 和 CS 抑制糖异生的分子机制；3) 确定 HNF4α 诱导 SULT2B1b 是否代表糖异生负反馈调节的潜在机制。据了解，本研究首次尝试全面评估 SULT2B1b 及其酶副产物 CS 在体内能量代谢中的内生功能和肝功能。可能会将 SULT2B1b 确立为新的治疗靶点，并将 CS 确立为管理代谢疾病的治疗剂。